Despite improvements in the past 20 years in glycemic and blood pressure control, and the introduction of 'renoprotective' drugs such as renin-angiotensin system blockers, the incidence of end-stage renal disease (ESRD) in type 1 diabetes (T1D) is not declining. Novel therapies to complement these interventions are urgently needed. Mounting evidence from prospective studies indicates that moderately elevated serum uric acid is a strong, independent predictor of an increased risk of chronic kidney disease and increased rates of loss of kidney function among T1D persons. To study whether uric acid lowering can reduce glomerular filtration rate (GFR) loss in T1D, we have established the PERL (Preventing Early Renal Function Loss in Diabetes) Consortium including investigators from the Joslin Diabetes Center, the Universities of Minnesota, Colorado, Toronto, and Michigan, and the Steno Diabetes Center in Denmark. With the support of NIH grant R03 DK094484, we have designed an international four-year, multi-center, double-blind, placebo- controlled, randomized clinical trial to evaluate the efficacy of the urate-lowering drug allopurinol, as compared to placebo, in reducing kidney function loss among subjects with T1D. The trial will include a total of 400 T1D patients at high risk for GFR loss because of increased albuminuria and a relatively high serum uric acid (e 4.5 mg/dl), who still have only mildly or moderately decreased renal function (GFR=45-99 ml/min/1.73 m2). The primary endpoint of the study will be the GFR (as measured by the iohexol plasma disappearance) at the end of the 4-year intervention. We have been recently funded by the Juvenile Diabetes Research Foundation to conduct a small pilot study in two centers (Joslin and Steno) with 30 subjects/group, which will establish the feasibilit of such a trial and pilot all of its clinical research procedures and data flow and management. With the R34 support, we intend to use this and other sources of information to bring this clinical trial closer to implementation by accomplishing the following Specific Aims: 1. To compile the Manual of Operations. 2. To obtain IRB approval at all study sites. 3. To develop recruitment strategies at each center, including the establishment of relationships with satellite centers. 4. To establish drug distribution centers for this international trial. 5. To develop the tools and infrastructure for data management, quality control, and research oversight. 6. To develop a data and safety monitoring plan. By accomplishing these aims, we will be ready to start recruiting patients for the pivotal trial as soon as this is funded. If we can demonstrate that allopurinol can halt or slow GFR decline in T1D subjects, we will have a simple, safe, and inexpensive intervention to prevent or delay kidney failure in T1D that can be applied at the earliest clinically detectable stages of renal injury. It is difficult to overstate how significantthis finding would be, both from the perspective of public health and that of persons with diabetes. PUBLIC HEALTH RELEVANCE: The trial that we propose, if successful, will introduce a new pharmacological intervention to prevent or delay kidney failure in T1D. The reduction in morbidity and mortality resulting from this would have a major impact on the lives of T1D patients as well as on society at large, significantly reducing the human and financial costs associated with this condition.